Ab initio structure of the active site of phosphotriesterase

This research exploits two recent developments to obtain a fundamental understanding of the metalloenzyme active site using the bimetallic enzyme phosphotriesterase as an example of this class. First is the theoretical prediction that the structure and spectroscopy of a native metalloenzyme active site is qualitatively determined by the supermolecule complex of the metal(s) and the first shell of ligands with proper charge states including waters directly bonded to ionic ligands. The second is the development of an effective potential for representing the molecular environment interacting with an all-electron active site in the quantum Hamiltonian. The GAMESS suite of electronic structure codes has implemented this new methodology, effective fragment potentials (EFP), to make theoretical calculations on structure, spectroscopy, and reactivity tractable for systems involving hundreds of atoms. Since there are transition metal cations at the active site of these enzymes, the all-electron part of the complex is calculated with relativistic compact effective potentials (CEP) and their concomitant basis sets. A realistic representation of the active site with its protein environment can be obtained using a combination of the CEP and EFP. This presentation will determine the inherent electronic and structural characteristics of phosphotriesterase using ab initio quantum mechanical methods. A single X-ray structure for the Zn-Zn enzyme is leveraged to obtain the structure of the Cd-Cd enzyme and to examine the consequences of protonating the active site.